Amyloid plaques and neurofibrillary tangles (NFT) are hallmarks of pathology in neurodegenerative disorders such as Alzheimer's disease (AD) (Braak et al., 2011, J. Neuropathol. Exp. Neurol. 70:960). NFT arise from phosphorylation of tau protein by a variety of kinases, including cAMP-dependent protein kinase (PKA) (Jicha et al., 1999, J. Neurosci. 19:7486). Hyperphosphorylation induces aggregation of tau into paired helical filaments (PHF), which in humans and rhesus monkeys can progress to NFT formation.
In AD, NFT selectively form in association cortices with the more extensive corticocortical connections between pyramidal cells (Bussière et al., 2003, J. Comp. Neurol. 463:281), as in layer III of the dorsolateral prefrontal association cortex (dlPFC), which is afflicted quite early and extensively in AD (Pearson et al., 1985, Proc. Natl. Acad. Sci. USA 82:4531). The numbers of NFT in association cortex correlate with the severity of dementia (Giannakopoulos et al, 2003, neurology 60:1495-1500), indicating that these signs of degeneration are linked to cognitive dysfunction. In contrast, primary sensory cortices (e.g., visual area V1) are little affected even in late disease (Pearson et al., 1985, Proc. Natl. Acad. Sci. USA 82:4531; Lewis et al., 1987, J. Neurosci. 7:1799). Studies of the nonhuman primate dlPFC have shown that these layer III pyramidal cell circuits interconnect on long, thin spines with glutamate NMDA-NR2B receptor excitatory synapses, and are extensively modulated by feedforward cAMP-Ca2+ signaling (Arnsten et al., 2012, Neuron 76:223).
Understanding why these circuits are selectively vulnerable to AD with advancing age is key to revealing disease etiology and thus developing strategies for intervention. Brains from individuals in their 40s and 50s displayed phosphorylated soluble tau in association cortex, indicating that the process may begin earlier than previously thought. Rodent AD models have provided a wealth of information regarding β-amyloid and tau signaling, but have not addressed this important issue, as rodents lack highly developed association cortices, and genetic alterations are introduced globally and do not mimic the pattern of pathology seen in humans (Platt et al., 2013, Biochim. Biophys. Acta 1832:1437).
Studies have shown evidence of mitochondrial dysfunction in AD, including reduced energy production and increases in reactive oxidation species (ROS) (Ferreira et al., 2010, Curr. Drug Targets 11:1193-1206). Excessive calcium release disrupts mitochondrial function (Mattson, 2010, Sci. Signal. 3:pe10; Camandola & Mattson, 2011, Biochim. Biophys. Acta:965-973), and recent findings suggest that increased cAMP-PKA activity with advancing age may also contribute to mitochondrial dysfunction. PKA phosphorylates cytochrome oxidase subunit IV (COXIV), which reduces ATP feedback and increases ROS production (Acin-Perez, et al., 2011, Cell Metab. 13:712-719).
There is a need in the art for novel methods of preventing or reducing risk of neurodegeneration of association cortex (or cortical degeneration) in a mammal in need thereof. Such methods may be used to prevent cognition loss in mammals that show no evident loss of cognitive abilities. The present invention fulfills these needs.